Novel Anti-Metastatic Action of Cidofovir Mediated by Inhibition of E6/E7, CXCR4 and Rho/ROCK Signaling in HPV+ Tumor Cells
Identifieur interne : 007B80 ( Main/Exploration ); précédent : 007B79; suivant : 007B81Novel Anti-Metastatic Action of Cidofovir Mediated by Inhibition of E6/E7, CXCR4 and Rho/ROCK Signaling in HPV+ Tumor Cells
Auteurs : Abdessamad Amine [France] ; Sofia Rivera [France] ; Paule Opolon [France] ; Mehdi Dekkal [France] ; Denis S. F. Biard [France] ; Hakim Bouamar [France] ; Fawzia Louache [France] ; Michael J. Mckay [Australie] ; Jean Bourhis [France] ; Eric Deutsch [France] ; Marie-Catherine Vozenin-Brotons [France]Source :
- PLoS ONE [ 1932-6203 ] ; 2009.
Abstract
Cervical cancer is frequently associated with HPV infection. The expression of E6 and E7 HPV oncoproteins is a key factor in its carcinogenicity and might also influence its virulence, including metastatic conversion. The cellular mechanisms involved in metastatic spread remain elusive, but pro-adhesive receptors and their ligands, such as SDF-1α and CXCR4 are implicated. In the present study, we assessed the possible relationship between SDF-1α/CXCR4 signaling, E6/E7 status and the metastatic process. We found that SDF-1α stimulated the invasion of E6/E7-positive cancer cell lines (HeLa and TC-1) in Matrigel though CXCR4 and subsequent Rho/ROCK activation. In pulmonary metastatic foci generated by TC-1 cells IV injection a high proportion of cells expressed membrane-associated CXCR4. In both cases models (
Url:
DOI: 10.1371/journal.pone.0005018
PubMed: 19325708
PubMed Central: 2657827
Affiliations:
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Le document en format XML
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<front><div type="abstract" xml:lang="en"><p>Cervical cancer is frequently associated with HPV infection. The expression of E6 and E7 HPV oncoproteins is a key factor in its carcinogenicity and might also influence its virulence, including metastatic conversion. The cellular mechanisms involved in metastatic spread remain elusive, but pro-adhesive receptors and their ligands, such as SDF-1α and CXCR4 are implicated. In the present study, we assessed the possible relationship between SDF-1α/CXCR4 signaling, E6/E7 status and the metastatic process. We found that SDF-1α stimulated the invasion of E6/E7-positive cancer cell lines (HeLa and TC-1) in Matrigel though CXCR4 and subsequent Rho/ROCK activation. In pulmonary metastatic foci generated by TC-1 cells IV injection a high proportion of cells expressed membrane-associated CXCR4. In both cases models (<italic>in vitro</italic>
and <italic>in vivo</italic>
) cell adhesion and invasion was abrogated by CXCR4 immunological blockade supporting a contribution of SDF-1α/CXCR4 to the metastatic process. E6 and E7 silencing using stable knock-down and the approved anti-viral agent, Cidofovir decreased CXCR4 gene expression as well as both, constitutive and SDF-1α-induced cell invasion. In addition, Cidofovir inhibited lung metastasis (both adhesion and invasion) supporting contribution of E6 and E7 oncoproteins to the metastatic process. Finally, potential signals activated downstream SDF-1α/CXCR4 and involved in lung homing of E6/E7-expressing tumor cells were investigated. The contribution of the Rho/ROCK pathway was suggested by the inhibitory effect triggered by Cidofovir and further confirmed using Y-27632 (a small molecule ROCK inhibitor). These data suggest a novel and highly translatable therapeutic approach to cervix cancer, by inhibition of adhesion and invasion of circulating HPV-positive tumor cells, using Cidofovir and/or ROCK inhibition.</p>
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<name sortKey="Bouamar, Hakim" sort="Bouamar, Hakim" uniqKey="Bouamar H" first="Hakim" last="Bouamar">Hakim Bouamar</name>
<name sortKey="Bourhis, Jean" sort="Bourhis, Jean" uniqKey="Bourhis J" first="Jean" last="Bourhis">Jean Bourhis</name>
<name sortKey="Dekkal, Mehdi" sort="Dekkal, Mehdi" uniqKey="Dekkal M" first="Mehdi" last="Dekkal">Mehdi Dekkal</name>
<name sortKey="Deutsch, Eric" sort="Deutsch, Eric" uniqKey="Deutsch E" first="Eric" last="Deutsch">Eric Deutsch</name>
<name sortKey="Louache, Fawzia" sort="Louache, Fawzia" uniqKey="Louache F" first="Fawzia" last="Louache">Fawzia Louache</name>
<name sortKey="Opolon, Paule" sort="Opolon, Paule" uniqKey="Opolon P" first="Paule" last="Opolon">Paule Opolon</name>
<name sortKey="Rivera, Sofia" sort="Rivera, Sofia" uniqKey="Rivera S" first="Sofia" last="Rivera">Sofia Rivera</name>
<name sortKey="Vozenin Brotons, Marie Catherine" sort="Vozenin Brotons, Marie Catherine" uniqKey="Vozenin Brotons M" first="Marie-Catherine" last="Vozenin-Brotons">Marie-Catherine Vozenin-Brotons</name>
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<country name="Australie"><noRegion><name sortKey="Mckay, Michael J" sort="Mckay, Michael J" uniqKey="Mckay M" first="Michael J." last="Mckay">Michael J. Mckay</name>
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